From various ureas and urea derivatives that have been synthesized in the past 2 years of this Grant 18 have been found to be sufficiently soluble in neutral aqueous solutions (solubility greater than 0.01 M) for further investigation. Among these compounds are some diureas, cycloalkylureas, and hydroxyureas with both aliphatic and aromatic side chains. The compounds that were found to be most effective denaturants were also the most effective inhibitors of hemoglobin S gelatin. These compounds are leucinol-l-urea-2, norleucinol-1-urea-2(1-hydroxyhexylurea-2), phenylalaninol-1-urea-2, and 8-hydorxyoctyl-urea-1 and are found to have saturation-solubility ratios at the 50 mM level, C50 sat/C0 sat of 1.17-1.23. The best noncovelent inhibitors examined by Behe and Englander (Biochemistry, 18,4196(1977) have C50 sat/C0 sat of about 1.18 to 1.21. Several of our most promising new compounds are 1-hydroxy-2-ureas, prepared from amino acids by a two-step reaction consisting of the diborane reduction of the amino acid to the corresponding alcohol followed by the conversion of the amino alcohol to the desired 1-hydroxy-2-urea using either sodium cyanate or nitrourea. The solubility of the 8-carbon side chain urea, 1-hydroxyoctylurea-2, prepared by this method was found to be less than 0.01 M, suggesting that the practical solubility limit in aqueous solutions has been reached with these compounds at the 8-carbon level. Preparation of the 7-carbon ureas (1-hydroxy-2-ureas and 1-hydroxy-7-urea) is in progress. We also plan to synthesize compounds of the urea family with appropriate spacer groups and solubilizing heteroatoms such as sulfur and oxygen incorporated in the aliphatic or aromatic side chains. Since phenylalaninol urea is a promising new antigelation compound, we plan to link alkyl or alkoxyl chains to the aromatic ring in order to see if its favorable properties are enhanced.